KDM6B Variants May Contribute to the Pathophysiology of Human Cerebral Folate Deficiency.

(1) Background: The genetic etiology of most patients with cerebral folate deficiency (CFD) remains poorly understood. variants were reported to cause neurodevelopmental diseases; however, the association between and CFD is unknown; (2) Methods: Exome sequencing (ES) was performed on 48 isolated CFD cases. The effect of variants on KDM6B protein expression, Histone H3 lysine 27 epigenetic modification and FOLR1 expression were examined in vitro. For each patient, serum FOLR1 autoantibodies were measured; (3) Results: Six variants were identified in five CFD patients, which accounts for 10% of our CFD cohort cases. Functional experiments indicated that these variants decreased the amount of KDM6B protein, which resulted in elevated H3K27me2, lower H3K27Ac and decreased FOLR1 protein concentrations. In addition, FOLR1 autoantibodies have been identified in serum; (4) Conclusion: Our study raises the possibility that may be a novel CFD candidate gene in humans. Variants in could downregulate FOLR1 gene expression, and might also predispose carriers to the development of FOLR1 autoantibodies.